AU4796693A - Crystalline amifostine compositions and methods for the preparation and use of same - Google Patents
Crystalline amifostine compositions and methods for the preparation and use of sameInfo
- Publication number
- AU4796693A AU4796693A AU47966/93A AU4796693A AU4796693A AU 4796693 A AU4796693 A AU 4796693A AU 47966/93 A AU47966/93 A AU 47966/93A AU 4796693 A AU4796693 A AU 4796693A AU 4796693 A AU4796693 A AU 4796693A
- Authority
- AU
- Australia
- Prior art keywords
- amifostine
- formulation
- crystalline
- temperature
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960001097 amifostine Drugs 0.000 title claims abstract description 206
- 239000000203 mixture Substances 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims description 68
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 title abstract description 168
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 22
- 239000007787 solid Substances 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 154
- 238000009472 formulation Methods 0.000 claims description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 74
- 239000000243 solution Substances 0.000 claims description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 23
- 229930195725 Mannitol Natural products 0.000 claims description 22
- 239000000594 mannitol Substances 0.000 claims description 22
- 235000010355 mannitol Nutrition 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 19
- 238000001291 vacuum drying Methods 0.000 claims description 19
- 239000013078 crystal Substances 0.000 claims description 17
- 238000001556 precipitation Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 13
- 229940126534 drug product Drugs 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 230000005496 eutectics Effects 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 238000000137 annealing Methods 0.000 claims description 7
- 150000004684 trihydrates Chemical class 0.000 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000008121 dextrose Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 230000001767 chemoprotection Effects 0.000 claims description 4
- 230000001950 radioprotection Effects 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 claims 44
- 238000010792 warming Methods 0.000 claims 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- -1 aminoalkyl dihydrogen Chemical compound 0.000 description 25
- 239000000047 product Substances 0.000 description 21
- 239000008186 active pharmaceutical agent Substances 0.000 description 18
- 229940088679 drug related substance Drugs 0.000 description 18
- 238000001035 drying Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 10
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 9
- 239000000523 sample Substances 0.000 description 8
- 238000003860 storage Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- YHPLKWQJMAYFCN-UHFFFAOYSA-N WR-1065 Chemical compound NCCCNCCS YHPLKWQJMAYFCN-UHFFFAOYSA-N 0.000 description 5
- 238000013480 data collection Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 239000008247 solid mixture Substances 0.000 description 5
- 239000012086 standard solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 150000003573 thiols Chemical class 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000012430 stability testing Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000012937 correction Methods 0.000 description 3
- 229940098617 ethyol Drugs 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005057 refrigeration Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-M hydron;thiophosphate Chemical compound OP(O)([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-M 0.000 description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 2
- 229960000367 inositol Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000718 radiation-protective agent Substances 0.000 description 2
- 229940124553 radioprotectant Drugs 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000009662 stress testing Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- WSKJXBGBFPSACA-UHFFFAOYSA-N 1-(2-aminoethylamino)ethylsulfanylphosphonic acid Chemical compound OP(=O)(O)SC(C)NCCN WSKJXBGBFPSACA-UHFFFAOYSA-N 0.000 description 1
- FFYTVSVIDULVND-UHFFFAOYSA-N 1-(5-aminopentylamino)ethylsulfanylphosphonic acid Chemical compound OP(=O)(O)SC(C)NCCCCCN FFYTVSVIDULVND-UHFFFAOYSA-N 0.000 description 1
- ZVBCJEKJBORTLM-UHFFFAOYSA-N 1-(6-aminohexylamino)ethylsulfanylphosphonic acid Chemical compound OP(=O)(O)SC(C)NCCCCCCN ZVBCJEKJBORTLM-UHFFFAOYSA-N 0.000 description 1
- CIZFDNUMIASEAV-UHFFFAOYSA-N 1-[3-(methylamino)propylamino]ethylsulfanylphosphonic acid Chemical compound CNCCCNC(C)SP(O)(O)=O CIZFDNUMIASEAV-UHFFFAOYSA-N 0.000 description 1
- 229940015297 1-octanesulfonic acid Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- BIQVLUUDYJRKIR-UHFFFAOYSA-N [2-(3-aminopropylamino)-2-methylpropyl]sulfanylphosphonic acid Chemical compound OP(=O)(O)SCC(C)(C)NCCCN BIQVLUUDYJRKIR-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000012611 container material Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 229940093495 ethanethiol Drugs 0.000 description 1
- OJZGWRZUOHSWMB-UHFFFAOYSA-N ethoxy-dihydroxy-sulfanylidene-$l^{5}-phosphane Chemical compound CCOP(O)(O)=S OJZGWRZUOHSWMB-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- WUOSYUHCXLQPQJ-UHFFFAOYSA-N n-(3-chlorophenyl)-n-methylacetamide Chemical class CC(=O)N(C)C1=CC=CC(Cl)=C1 WUOSYUHCXLQPQJ-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011734 sodium Chemical class 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
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Abstract
The present invention relates to a sterile, stable vacuum dried crystalline amifostine composition and, optionally, pharmaceutically acceptable excipient(s). Typically, the crystalline compositions of the present invention exhibit enhanced stability at temperatures ranging from about 4 DEG C. to about ambient temperature for a period of at least 2 years relative to existing solid vacuum dried amorphous amifostine preparations. The reconstituted compositions of the present invention are suitable for administration to humans as a radio- or chemoprotecting agent.
Description
CRYSTALLINE AMIFOSTINE COMPOSITIONS AND
METHODS FOR THE PREPARATION AND USE OF SAME
1. FIELD OF THE INVENTION
The present invention relates to sterile,
particulate-free crystalline S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (amifostine)
formulations which provide improved stability.
2. BACKGROUND OF THE INVENTION The compound S-2-(3-aminopropylamino) ethyl dihydrogen phosphorothioate (which is also known as amifostine, ethiofos, Ethyol®, NSC 296961, and WR-2721 and which will hereinafter be referred to as
"amifostine") and other aminoalkyl dihydrogen
phosphorothioates are disclosed in United States
Patent No. 3,892,824 to Piper et al. This patent also discloses the known process for making a crystalline form of amifostine drug substance and is incorporated herein by reference. This crystalline form of
amifostine has been shown to be relatively stable at room temperature for several years as well as at 50°C for several months. These compounds were originally developed as antiradiation agents (radioprotectants), in particular to be used against x-ray or nuclear radiation which may be encountered during military conflicts.
In addition to its utility as a military
antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant i.e., as a protectant for the undesirable adverse effects which arise during the use of radiation therapy in the treatment of cancer and the use of chemotherapeutic agents, for example, alkylating agents such as cyclophosphamide, cisplatin, carboplatin, doxorubicin and its derivatives, and
mitomycin and its derivatives. Similarly, it has been reported that amifostine has been used experimentally to protect HIV infected patients (AIDS) from the harmful side effects of 3'-azido-3'-deoxythymidine (AZT) therapy. Amifostine and its derivatives exert their protective effects without significantly
affecting the beneficial properties of the
administered therapeutic agents. This is in part due to the selective uptake of the protective thiol into normal tissue.
As used herein, the term "amifostine drug
substance" refers to its pre-vacuum dried or prevacuum dried state which is available on an "as is" basis in a trihydrate form. Currently available sterile, vacuum dried formulations of amifostine drug product will be referred to as "amorphous amifostine", whereas the form covered by the present invention will be referred to as "crystalline amifostine" in order to distinguish between the two forms. Unless otherwise specified, quantities reported herein shall be
calculated on an anhydrous basis.
Although amifostine has many advantageous
properties, extensive difficulty has been encountered in trying to obtain a convenient, stable, sterile dosage formulation.
The present manner of manufacturing and
packaging amifostine comprises the steps of filling into pre-sterlized vials a sterilized water solution comprising amifostine to a predetermined volume, cooling the vials and their contents, and removing the solvent by lyophilization to produce dried amifostine of a predetermined amount in each vial. [See L.
Lachman, et al. The Theory and Practice of Industrial Pharmacy p 62-63, 1986]. This avoids substantial practical problems related to the packaging of bulk,
solid amifostine using the so-called "dry filling" or "powder filling" method. Such problems include the difficulty in the manual manipulation of powders, the need to mill the powders to acceptable particle size and flowability, difficulty in maintaining particle-free, aseptic conditions, and the difficulty in supplying the precise dosage of solid amifostine into each vial.
However, the currently available formulation of amifostine. This amorphous form that is produced by lyophilization is thermally unstable. As a result, this lyophilized formulation must be maintained at temperatures at about -20°C and shipped at
temperatures at about -70°C to about -20°C to avoid degradation of the formulated product. The need for low temperature during shipping and storage is an obstacle and shortcoming of currently available vacuum dried forms of amifostine. Special packaging and significant expenses are involved in the shipping and storage of the product. Moreover, hospitals without freezer storage conditions will be unable to supply amifostine for use to their patients (e.g., third world markets would be extensively hindered from using amifostine). However, since no alternative
formulations were available, clinical trials were conducted using this formulation.
Hence, there is a need to develop a dosage form which has sufficient stability to provide a long shelf life at room temperature or under less stringent refrigeration, which is not uncommon for many drug products.
The present invention describes new and novel procedures which produce solid compositions containing vacuum dried amifostine, with and without
pharmaceutically acceptable excipients such as
mannitol, which have improved stability over the previously available composition.
3. SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of crystalline compositions comprising the steps of (a) preparing a formulation comprising an aminoalkyl dihydrogen phosphorothioate of the formula RHN(CH2)nNH(CH2)mSPO3H2 or its hydrates or alkali metal salts, in which R is H or C1-C7 alkyl, and n and m may be independently an integer from 2-6, an alcohol and water solvent solution in which the relative amounts of aminoalkyl dihydrogen phosphorothioate, alcohol and water are such that a particulate-free solution is obtained at temperatures ranging from about room temperature to about 10°C, but which provides a crystalline precipitate of aminoalkyl dihydrogen phosphorothioate upon cooling below 0°C; (b) cooling the formulation to a temperature below 0°C for a period of time sufficient to effect the precipitation of the crystalline aminoalkyl dihydrogen
phosphorothioate; and (c) vacuum drying the resulting mixture to leave a solid crystalline preparation having an enhanced temperature stability. As a further step in the present invention, a sterile inert gas such as argon, nitrogen and helium can be
introduced over the preparation. Preferably, the temperature to which the formulation is cooled to initiate precipitation of the crystalline aminoalkyl dihydrogen phosphorothioate is in the range of the eutectic point of the formulation. Optimally, the formulation may also contain excipients such as mannitol.
Aminoalkyl dihydrogen phosphorothioates suitable for use in the present invention include, but are not
limited to, S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (amifostine) , S-2- ( 3-methylaminopropylamino) ethyl dihydrogen
phosphorothioate (WR-3689), S-2-(3-ethylaminopropylamino)ethyl dihydrogen
phosphorothioate, S-2-(3-aminopropylamino)-2-methylpropyl dihydrogen phosphorothioate, S-2-(2-aminoethylamino)-2-ethyl dihydrogen phosphorothioate, S-2-(4-aminobutylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(5-aminopentylamino)-2-ethyl dihydrogen phosphorothioate, S-2-(6-aminohexylamino)-2-ethyl dihydrogen phosphorothioate, S-2-(2-methylaminoethylamino)-2-ethyl dihydrogen
phosphorothioate, S-2-(3-methylaminopropylamino)-2-ethyl dihydrogen phosphorothioate, and S-3-(3-methylaminopropylamino)-3-propyl dihydrogen
phosphorothioate (WR-151327). In a preferred
embodiment, the aminoalkyl dihydrogen phosphorothioate is amifostine, WR-3689, WR-151327, most preferably amifostine. Alcohols suitable to effect crystalline precipitation of aminoalkyl dihydrogen
phosphorothioate for use in the present process include, but are not limited to, C1-C5 alkyl alcohols, such as methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, 2-pentanol, and the like, preferably ethanol.
In a particular process of the invention, the temperature of the mixture resulting from step (b) is raised to an annealing temperature that lies about 1 to about 20°C above the eutectic temperature of the formulation, followed by cooling the temperature of the mixture from the annealing temperature back to the eutectic temperature or below prior to performing the vacuum drying of step (c). In specific instances, the eutectic temperature may fall in the range of about
-80°C to about 0°C, while the annealing temperature may fall in the range of about -30°C to about 10ºC.
Thus, it is an objective of the present invention to provide a process in which the formulation
comprises about 50 to about 400 mg aminoalkyl
dihydrogen phosphorothioate per ml of formulation, about 1-35% (v/v) alcohol, and about 65-99% (v/v) water. Preferably, the formulation comprises about 125 to about 250 mg aminoalkyl dihydrogen
phosphorothioate per ml of formulation, about 5-20% (v/v) alcohol, and about 80-95% (v/v) water. Most preferably, the formulation comprises about 100 mg aminoalkyl dihydrogen phosphorothioate per ml of formulation, about 10 % (v/v) alcohol, and about 90 % (v/v) water.
The temperatures of the various cooling and vacuum drying steps can vary widely depending on the specific ratios of aminoalkyl dihydrogen
phosphorothioate to alcohol to water. Generally, however, the temperatures of steps (b) and (c) fall in the range of about -40°C to about -5°C, preferably about -20°C.
In a specific embodiment of the present
invention, the process includes a sterilization step. Sterilization may be effected in any number of ways well know to those skilled in the art, such as heating the mixture in an autoclave, treatment with gamma radiation, aseptic recrystallization, or sterile filtering a solution, e.g., through a 0.2 μm pore size filter. It should be noted further that the
crystalline aminoalkyl dihydrogen phosphorothioate may be anhydrous or contain solvents of crystallization. In particular, crystalline amifostine may be
anhydrous, a solvate, or a hydrate, such as a
monohydrate or a trihydrate. Generally, the hydrates
may contain about 1 to about 5 , preferably about 1 to about 3, moles of water of crystallization.
In an alternative procedure for preparing the formulation, the aminoalkyl dihydrogen
phosphorothioate, such as amifostine, and any desired excipients are dissolved in Water for Injection, USP, and the resulting solution is then sterile filtered. Thereafter, the required amount of sterile alcohol such as sterile ethanol, USP is added to yield the formulation that is subsequently subjected to the cooling or annealing steps.
The formulation produced according to the
disclosed process may further be comprised of a pharmaceutically acceptable excipient. Suitable excipients include, but are not limited to, sodium chloride, propylene glycol, sucrose, dextrose, sorbitol, inositol, mannitol, glycine, arginine, or other amino acids, preferably mannitol, and most preferably mannitol, NF.
Thus, it is a particular objective of the present invention to provide a process for the preparation of a pharmaceutical composition containing crystalline amifostine comprising the steps of (a) preparing a formulation comprising about 50 to about 300 mg amifostine per ml of the formulation, about 3 to about 30% (v/v) ethanol, about 70-97% (v/v) water, and, optionally, about 5 to about 300 mg of a
pharmaceutically acceptable excipient per ml of the formulation, such that a particulate-free solution is obtained at temperatures ranging from about room temperature to about 10°C, but which provides a crystalline precipitate of amifostine upon cooling below 0°C; (b) cooling the formulation to a
temperature falling in the range of about -40°C to about -5°C for a period of time sufficient to effect
the precipitation of the crystalline amifostine; and (c) vacuum drying the resulting mixture to leave a solid crystalline amifostine preparation having an enhanced temperature stability. In general, the steps taken after step (a) and before step (c) are carried out over a period of about 0.5 to about 72 hours, preferably about 2 to about 24 hours. Those
manipulations taken at step (c) are carried out over a period of about 1 to about 72 hours, preferably about 10 to about 20 hours. In addition, the vacuum drying of step (c) is carried out at a vacuum of about 10 to about 1000 mTorr, preferably 150 mTorr.
Yet another object of the present invention concerns the preparation of a sterile pharmaceutical composition having an enhanced temperature stability in which the active ingredient, i.e., the crystalline aminoalkyl dihydrogen phosphorothioate, such as amifostine, remains stable at about 4°C for at least 2 years. Preferably, the crystalline aminoalkyl
dihydrogen phosphorothioate, such as amifostine, remains stable at about ambient temperature for at least 2 years. Thus, a sterile composition having an enhanced temperature stability is provided, which composition comprises a crystalline amifostine which can be reconstituted with a pharmaceutically
acceptable vehicle into an injectable particulate-free drug product. Preferably, the sterile, composition is provided as a sterile single dose formulation having an enhanced temperature stability comprising about 10 to about 10,000 mg crystalline amifostine and, optionally, about 10 to about 10,000 mg of a
pharmaceutically acceptable excipient, which
formulation can be reconstituted with a
pharmaceutically acceptable vehicle into an injectable particulate-free drug product. In a more preferred
embodiment, the sterile single dose formulation comprises about 100 to about 1000 mg crystalline amifostine and about 100 to about 1000 mg of an excipient. Most preferably, the sterile single dosage formulation comprises about 500 mg crystalline
amifostine and about 500 mg mannitol. The vehicle may be chosen from a wide variety of pharmaceutically acceptable vehicles and may include Water for
Injection, USP, Normal Saline, USP, 5% Dextrose in Water, USP, or aqueous buffers.
A further object of the present invention
includes a method of treating a subject in need of radio- or chemoprotection, which comprises
administering to the subject an effective amount of a pharmaceutical composition containing a crystalline aminoalkyl dihydrogen phosphorothioate having the generic chemical formula described above, such as amifostine, which has been reconstituted with a pharmaceutically acceptable vehicle. The
reconstituted pharmaceutical composition may be administered parenterally. If desired, the
reconstituted pharmaceutical composition may be administered intravenously, intramuscularly,
subcutaneously, intracavetarily, and intrathecally.
These and other objects of the invention should be apparent to one of ordinary skill in the art from a reading of the general and detailed descriptions provided herein.
4. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 Graph of Amifostine Drug Substance (WR- 2721) Solubility in Aqueous/Ethanol Solutions vs. Temperature (°C)
Figure 2 Graph of the Dependence of Amifostine
Drug Substance Solubility on Ethanol Concentration
Figure 3 TGA of Crystalline Amifostine Drug
Product Formulated From 10% Ethanol in Water
Figure 4 TGA of Amifostine Drug Substance
Figure 5 DSC of Crystalline Amifostine Drug
Product Formulated From 10% Ethanol in Water
Figure 6 DSC of Amifostine Drug Substance
Figure 7 FTIR of Crystalline Amifostine Drug
Product Formulated From 10% Ethanol in Water
Figure 8 FTIR of Amifostine Drug Substance
Figure 9 X-ray Diffraction of Crystalline
Amifostine Drug Product Formulated From 10% Ethanol in Water
Figure 10 X-ray Diffraction of Amifostine Drug
Substance
Figure 11 TGA of Crystalline Amifostine and
Mannitol Drug Product Formulated From 10% Ethanol in Water
Figure 12 DSC of Crystalline Amifostine and
Mannitol Drug Product Formulated From 10% Ethanol in Water
Figure 13 depicts the molecular and crystal
structure of vacuum dried amifostine
5. DETAILED DESCRIPTION OF THE INVENTION Prior to the present invention, the available pharmaceutical formulation of amifostine (Ethyol®) was thermally unstable. Because of its instability, the Ethyol® formulation required the use of low
temperatures during shipping and storage in order to prevent product degradation.
The present invention provides the first stable, vacuum dried pharmaceutical formulation of amifostine which can be conveniently handled and stored at temperatures from about 4°C to about room temperature for long periods of time without significant product degradation, thus providing a solution to a long sought need. The formulation will allow amifostine drug product to be shipped to and stored in hospitals around the world which do not have freezer storage capabilities required for the currently available formulation.
Unexpectedly, it has been discovered that a sterile and stable product of crystalline amifostine with and without excipient (s) such as mannitol can be prepared from the vacuum drying of an amifostine drug substance-containing hydro-ethanolic solution of about 1 to about 35% ethanol.
An important aspect of the present invention involved preformulation studies that determined
(1) the solubility of amifostine drug substance
(mg/ml) at various concentrations of water/ethanol,
(2) the solubility of amifostine drug substance in water/ethanol at various temperatures, (3) the
appropriate shelf temperature of the freeze-dryer needed to effect precipitation of amifostine before vacuum drying and (4) the concentration of ethanol needed in the formulation to give a super-saturated solution that when cooled to the desired shelf temperature in the freeze-dryer results in the precipitation of amifostine in a crystalline form. From the above preformulation studies (see Examples, infra) it was determined that the preferred
concentration of amifostine, on an anhydrous basis,
was about 100 mg/ml in about 10% aqueous ethanol.
Further, a preferred shelf temperature of about -20°C would effect precipitation of amifostine.
In order to obtain an elegant cake product, the percentage of ethanol in the ethanol/water mixture ranges from about 1 to about 35% v/v of ethanol (e.g., ratio of ethanol:water 1:99; 35:65); similarly, the shelf temperature of the freeze-dryer can range from about -40°C to about -10°C, preferably -20°C. The results of the preformulation studies presented in this invention provide an important basis for
adjustment of the interdependent variables of
amifostine concentration, ethanol concentration and temperature to provide for multiple container
size/fill volume combinations.
Generally, the freeze-dryer shelf is pre-chilled to a temperature of about -30°C to about -15°C, preferably about -20°C. The vials are loaded and the temperature is readjusted to about -30°C to about -15°C and preferably -20°C and the vials are
maintained at this temperature for about 20 hours. Depending on the concentration of ethanol and
amifostine or amifostine and excipient in the
solutions, and depending on ethanol concentration, the temperature necessary to effect precipitation will vary accordingly. Next, the precipitation of
crystalline amifostine takes place, followed by the freezing of the formulation.
Once the frozen formulation is observed, the primary drying cycle is initiated to remove bulk water and ethanol. Generally, the pressure in the chamber is reduced to about 150 mTorr. The primary drying cycle is complete when the formulation temperature was approximately -20±2°C for more than two hours. During the secondary drying process, the formulation is held
at about -20°C to about 10°C, preferably at a
temperature above the primary drying cycle
temperature, for about 40 to about 50 hours to
facilitate secondary drying, i.e. removal of residual water and ethanol. When the partial pressures of water and ethanol in the chamber reaches a steady state, the drying is considered to be completed.
These formulations provide a vacuum dried product which has been found to be a crystalline amifostine that demonstrates improved stability over the current formulation which contains amorphous amifostine. The vials can then be stored and shipped at temperatures from about 4°C to about room temperature without significant product degradation.
Moreover, excipients can be added to increase the amount of solids present in the formulation. Among the excipients found useful for this purpose, often in combination, are sodium or potassium phosphates, sodium chloride, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, sucrose, sorbitol, inositol, mannitol and dextran. In addition to those mentioned herein others are known to those skilled in the art.
The vacuum dried crystalline amifostine solid compositions of the present invention may be provided in single dose container forms by aseptically filling suitable containers with the sterile pre-vacuum dried solution to a prescribed amifostine content; preparing the desired vacuum dried solid composition; and then hermetically sealing the single dose container. It is intended that these filled containers will allow rapid dissolution of the solid composition upon
reconstitution with appropriate sterile diluents in situ giving an appropriate sterile solution of desired amifostine concentration for administration. As used
herein, the term "suitable containers" means a
container capable of maintaining a sterile
environment, such as a vial, capable of delivering a vacuum dried product hermetically sealed by a stopper means. Additionally, suitable containers implies appropriateness of size, considering the volume of solution to be held upon reconstitution of the vacuum dried composition; and appropriateness of container material, generally Type I glass. The stopper means employed, e.g., sterile rubber closures or an
equivalent, should be understood to be that which provides the aforementioned seal, but which also allows entry for the purpose of introduction of diluent, e.g., sterile Water for Injection, USP,
Normal Saline, USP, or 5% Dextrose in Water, USP, for the reconstitution of the desired amifostine solution. These and other aspects of the suitability of
containers for pharmaceutical products such as those of the instant invention are well known to those skilled in the practice of pharmaceutical arts.
While the physical properties, such as
appearance, were improved in the instant solid
compositions, thereby achieving one objective of the invention, we unexpectedly found that these instant solid compositions also possessed improved thermal stability compared with currently known formulation. In practice, expectation for enhancement of chemical stability by vacuum drying relates to a comparison of the stability of the vacuum dried solid with the stability of the solution form of the pharmaceutical composition. In contrast, the instant compositions demonstrate enhanced chemical stability between solid dosage forms, see Examples infra.
The pharmaceutical compositions of the present invention are suitable for parenteral administration,
for example, intravenous, intramuscular,
intracavitary, intrathecal, and subcutaneous
inj ections .
The following examples are intended to be
illustrative of the present invention and should not be construed, in any way, to be a limitation thereof.
6. EXAMPLES
EXAMPLE 1: PROCEDURE FOR PREFORMULATION STUDIES This example provides the procedure used for the preformulation studies which were designed to evaluate the appropriate parameters, i.e. amifostine
concentration, ethanol concentration and temperature, for obtaining a sterile vacuum dried form of
crystalline amifostine with and without
pharmaceutically acceptable excipients using vacuum drying from a water/ethanol mixture.
A. Preparation of Sample Solutions
In separate test tubes with screw caps add the following:
(a) 5000 μL water
(b) 4750 μL water and 250 μL ethanol
(c) 4500 μL water and 500 μL ethanol
(d) 4250 μL water and 750 μL ethanol
(e) 4000 μL water and 1000 μL ethanol
Add amifostine to each test tube until the solid remains undissolved. Sonicate for 30 seconds. If all the amifostine has dissolved, add an additional amount of drug substance until particles remain undissolved in the solvent. Vigorously shake the test tubes for 30 minutes at 25°C.
B. Preparation of Standard Solutions
Prepare 10 mL of the of the following solutions of Drug Substance in water:
(a) 0.05 mg/mL
(b) 0.1 mg/mL
( c ) 0 . 3 mg/mL
( d ) 0 . 5 mg/mL
On a UV spectrophotometer, scan each solution against a water blank over a range of 190 - 290 nm. Record the absorbance at 200 nm or 210 nm. Perform linear regression analysis of standard data at 200 nm or 210 nm and obtain a slope and intercept value.
C. Analysis of Sample Solutions
Remove approximately 0.5 mL of each solution and centrifuge to pellet solids. Filter each sample with 0.45 μm filter to remove excess particles if
necessary. Dilute each sample to a working
concentration of 0.3 to 0.4 mg/mL with water. On the UV Spectrophotometer scan each sample over a range of 190 - 290 nm. Obtain a reading for each sample at 200 nm or 210 nm. From the standard slope and intercept and dilutions, calculate the concentration of
amifostine in each solution. Cool the solutions to the next lowest temperature and repeat above after solution is at temperature for 1 hour. Table 1 provides the results of the solubility runs of amifostine in ethanol/water mixtures at various temperatures. This relationship is graphically demonstrated in Figures 1 and 2.
This example demonstrates that the solubility of amifostine drug substance is strongly dependent on both the ethanol co-solvent content and temperature. Generally, the degree of supersaturation resulting from a drop in the temperature of a given amifostine solution decreases with increasing ethanol co-solvent content (see Table 1 and Figures 1 and 2). This dependence is exploited in the following Examples 2 and 3 to achieve crystalline amifostine.
EXAMPLE 2 METHOD OF PRODUCING CRYSTALLINE
AMIFOSTINE WITHOUT MANNITOL
To 130 mL of water at 25°C, add with stirring 21.25 gm of amifostine drug substance trihydrate, which is equivalent to 17.0 gm of anhydrous amifostine drug substance. After dissolution of amifostine drug substance is complete, 17 mL absolute ethanol, USP, is added to the solution with stirring. Water is then added to QS 170 mL. The resulting solution is sterile filtered through a 0.22 μm filter. To each of thirtythree 10 mL vials, is dispensed 5 mL of the filtered solution to give 500 mg amifostine, on an anhydrous basis, per vial in an ethanol:water ratio of 10:90. Split stoppers are placed on the vials and the samples are subjected to the following vacuum drying cycle: the samples are placed on the shelves of the freeze
dryer, which has been pre-cooled to about -20°C, for about 17 hours at ambient pressure, after which time the chamber is evacuated and the shelves are held at about -20°C for 28 hours. Following this period, the chamber is back-filled with nitrogen and the vials are quickly stoppered by hand. This procedure results in a thermally-stable, freeze-dried single dose vial containing approximately 500 mg of crystalline
amifostine as an elegant cake.
EXAMPLE 3: METHOD OF PRODUCING CRYSTALLINE
AMIFOSTINE
Approximately 20 grams of mannitol is added with stirring to 150 mL of water at 25°C. To this solution is added, with stirring, approximately 25 grams amifostine drug substance (trihydrate basis), which is equivalent to 20 grams of anhydrous amifostine drug substance. After dissolution is complete, 20 mL of anhydrous ethanol, USP, is added volumetrically to the solution with stirring. Water is added QS to 200 mL. The resulting solution is sterile filtered through a 0.2μm filter and 5 mL of solution is transferred to each of 40 10-mL vials. Split stoppers are placed on the vials and the samples are loaded onto the freeze-dryer shelf at ambient temperatures. The shelf temperature is decreased at 2°C/min to -25°C and held at this temperature for 90 minutes to initiate
amifostine crystallization. After this time, the shelf temperature is raised above the eutectic point at a rate of 2°C/min to -5°C and held at this
temperature for 10 hours to anneal the product.
Subsequently, the shelf temperature is lowered to -25°C until the product temperature is less than -18°C for greater than 60 minutes. After this time, the freeze-dryer condenser is turned on and the vacuum in the chamber is lowered to 150 mTorr. The shelf-
temperature is raised to -20°C and the samples are allowed to vacuum dry for 14 hours. At this point, the monitored vials have reached shelf temperature, indicating the end of the primary drying cycle. The vials remain at 150 mTorr on the -20°C shelf for an additional 13.4 hours to ensure the removal of nonhydrate water. The chamber is back-filled with nitrogen and the vials are mechanically stoppered. This procedure results in a thermally-stable, vacuum-dried single dose vial containing approximately 500 mg of amifostine (anhydrous basis) and 500 mg mannitol as an elegant cake.
EXAMPLE 4: VACUUM DRIED CRYSTALLINE AMIFOSTINE
STABILITY TESTING
Several sealed, nitrogen-filled vials of
crystalline amifostine formulated from 10:90
ethanol: water, as described in Example 2 above, are stressed at 50°C for up to 35 days to determine the thermal stability of the crystalline amifostine.
The results are tabulated in Table 2 below. All data are reported as percent (%) of initial
concentration, which is defined as 100%.
TABLE 2
TIME AT 50°C
STUDY (IN DAYS) % OF INITIAL CONCENTRATION
1 0 100.0
3 106.3
35 96.9
2 0 100.0
3 97.2
7 101.1
14 93.9
21 71.1
0 100.0
3 103.6
7 101.8
14 97.5
21 86.7
For comparison purposes, the current amorphous amifostine formulation is also subjected to stress testing at 50°C for up to 28 days. The results are presented in Table 3 below. All data are reported as percent (%) of initial concentration, which is defined as 100%.
TABLE 3
TIME AT 50ºC
STUDY (IN DAYS) % OF INITIAL CONCENTRATION
1 0 100.0
14 2.8
28 1.5
2 0 100.0
14 2.0
28 1.4
3 0 100.0
14 1.7
28 1.4
Hence, it is abundantly clear that, even between solid formulations, a dramatic increase in thermal stability is achieved by crystalline compositions obtained from the disclosed process.
EXAMPLE 5: PREFERRED METHOD OF PRODUCING
CRYSTALLINE AMIFOSTINE
Compounding Procedure for Amifostine/Mannitol
(100 mg anydrous each/mL)
The following procedure was written to yield 3.5 liters of solution.
1. 350 grams mannitol (USP) were dissolved with
stirring (magnetic teflon stir bar) in about 2300 mL Nanopure water at room temperature in a stainless steel pressure vessel.
2. 438.3 grams amifostine trihydrate was added to this solution. Dissolution was aided with vigorous stirring.
3. After amifostine dissolution were complete, 525 mL dehydrated ethanol (USP) was slowly added to the solution with vigorous stirring. Amifostine precipitation occurs at the addition site
followed by rapid re-dissolution as the ethanol is diluted by stirring.
4. After the addition of the ethanol is complete, the solution was diluted to 3500 mL with Nanopure water.
5. The solution was filtered under a positive
pressure of 10 psi (nitrogen) through a
Millipore-40 filter.
6. 5 mL of the resulting solution was transferred to each of 660 10-mL tubing vials (Wheaton E-2910- B47B). The vials were partially seated with grey butyl rubber stoppers (Tompkins PT23B0857 F2) and vacuum dried.
Vacuum drying Cycle for Amifostine/Mannitol
(100 mg anhydrous /mL)
1. Vials are placed on the shelf at about 25°C to insure that amifostine precipitation is not initiated heterogeneously.
2. The shelf temperature is lowered at 2°C per minute to -35°C. Once this shelf
temperature is obtained, it is held constant for 240 minutes to insure solution freezing of all vials. During this stage the samples pass through a eutectic (approximately
-16°C).
3. At the end of the 240 minute hold time, the shelf temperature is raised at 2°C per minute to 0°C over 25 minutes. Once this shelf temperature is obtained, it is held constant for 600 minutes.
4. At the end of the 600 minute hold time, the shelf temperature is again lowered to -35°C at 2°C per minute. Once this temperature is obtained, it is held constant for 180 minutes.
5. After this time, the condenser is turned on.
When the condenser temperature is less than -40°C, the chamber is evacuated. When the chamber pressure is less than 150 mT, the shelf temperature is raised to -20°C at 2°C per minute and the chamber pressure is held at 150 mT with a nitrogen chamber bleed.
6. The product is left in the chamber at 150 mT for 12 to 24 hours after the monitored product temperature has reached shelf
temperature. The chamber is back-filled with nitrogen and the vials stoppered.
NOTE: 1 Torr is equivalent to 1 millimeter of Hg at 0°C.
Sealed, nitrogen-filled 10 ml tubing vials containing vacuum dried crystalline amifostine, obtained as described in Example 5, were stressed at 40°C for 4 weeks. For crystalline amifostine dried at -20°C for 12 hours, 93% of the amifostine remained at the end of the stress test period. For cystalline amifostine dried at -20°C for 24 hours, 84% of the amifostine remained at the end of the stress test period. EXAMPLE 6: MOST PREFERRED METHOD OF PRODUCING
CRYSTALLINE AMIFOSTINE
It was found that the most stable vacuum dried, crystalline amifostine was obtained by vacuum-drying an amifostine/mannitol, ethanol/water solution containing 15% v/v ethanol. The compound procedure is the same as described in Example 5 except for the lesser amount of dehydrated ethanol added to the solution.
The specific manner of conducting the vacuum drying cycle to produce the most stable crystalline amifostine was arrived at after several studies were performed to evaluate effects of changing the final drying temperature, the time period for final drying, and the rate of initial cooling to -35°C of the solution-containing vials. It was found that in general, the stability of crystalline amifostine is the greatest when the final drying temperature was at -20°C, and the time for the final drying was between 12 and 24 hours. Additionally, the stability of the crystalline amifostine was higher when the initial
cooling to -35°C of the solution-containing vials was conducted in 160 minutes rather then 45 minutes.
Based on the above development studies, the most preferred manner of conducting the vacuum drying cycle is as follows:
Vacuum drying Cycle for Amifostine/Mannitol
(100 mg anhydrous /mL) 1. Vials are placed on the shelf at about 25°C to insure that amifostine precipitation is not initiated heterogeneously.
2. The shelf temperature is lowered from 25°C to 0°C in 20 minutes, 0° to -20°C in 60 minutes, and then from -20 °C to -35 °C in 80 minutes. Once the shelf temperature is obtained, it is held constant for 240 minutes to insure solution freezing of all vials. During this stage the samples pass through a eutectic (approximately -16°C). 3. At the end of the 240 minute hold time, the shelf temperature is raised to 0°C over 25 minutes. Once the shelf temperature of 0°C is obtained, it is held constant for 600 minutes.
4. At the end of the 600 minute hold time, the shelf temperature is again lowered from 0°C to -15°C in 15 minutes, and then from -15°C to -35°C in 120 minutes. Once the temperature of -35°C is obtained, it is held constant for 180 minutes.
5. After this time, the condenser is turned on.
When the condenser temperature is less than -40°C, the chamber is evacuated. When the chamber pressure is less than 150 mT, the shelf temperature is raised from -35°C to -
20°C at 2°C per minute while the chamber pressure is held at 150 mT with a nitrogen chamber bleed.
6. The product in the vials is left in the
chamber at 150 mT for 12 to 24 hours after the monitored product temperature has reached shelf temperature. The chamber is back-filled with nitrogen and the vials stoppered.
NOTE: 1 Torr is equivalent to 1 millimeter of Hg at 0°C.
Without wishing to be limited by theory, it is believed that above step 2 causes the formation of seed crystals of amifostine in the frozen solution and step 3 causes the growth of amifostine crystals around the seed crystals and ensures completion of the crystallization of amifostine from the partially frozen solution.
Crystalline amifostine has been produced using the above vacuum drying cycle, utilizing 12.5% ethanol solution - - one produced with a f inal drying step of 12 hours and another produced with a final drying step of 24 hours. Stress testing of these two products at 40°C for eight weeks indicate no
perceptible decomposition of amifostine for the product dried for 12 hours, and a 2% decomposition of amifostine for the product dried for 24 hours.
EXAMPLE 7: PREFERRED MANNER OF CONDUCTING
CRYSTALLINE AMIFOSTINE STABILITY TESTING
Sealed, nitrogen-filled 10 ml tubing vials containing vacuum dried crystalline amifostine,
obtained as described in Example 6, were stressed at 40°C for up to eight weeks.
It was found that previous stability testing at 50°C caused decomposition of the crystalline
amifostine in the sealed vials in a manner not easily correlated to the stability of the crystalline
amifostine under typical storage conditions (i.e. at refrigeration temperature of about 4°C). However, results of stability testing at 40°C and less can be correlated to the stability of crystalline amifostine under typical storage conditions. As an
approximation, stability for one month at 30°C
correlates to eighteen months at 4°C; stability for 2-3 weeks at 40°C correlates to 18 months at 4°C; and stability for 8 - 12 weeks at 40°C correlates to 18 months at 25°C. See L. Lachman, et al. The Theory and Practice of Industrial Pharmacy pages 766-67 for a general discussion of stability prediction.
At the end of the stress period, the crystalline amifostine in the vials was tested for water content, thiol content, and amifostine content. The water content was determined by Karl Fischer titration.
Because amifostine may undergo hydrolysis under stress to produce 2 -[(3 - aminopropyl) amino] ethane thiol and phosphoric acid, determination of the amount of this thiol gives an indication of the stability of the amifostine. Analysis of thiol and amifostine content was conducted using the following procedure:
1. Preparation of Standards and Samples
Weight and volumes may be adjusted provided the final concentrations remain the same. Store solutions under refrigeration and/or in a refrigerated autosampler immediately after preparation.
1.1 Preparation of Amifostine Standard
solutions (3 mg/mL, Methanol/Water
[50/50])
Accurately weigh aproximately 30.0 mg of amifostine standarded into a 10-mL volumetric flask. Dissolve in 5 mL of water and dilute to volume with methanol. Shelf-Life: 24 hours at 4°C 1.2 Preparation of 2-[(3-amino
propyl)amino] ethanethiol,
dihydrochloride
Standard Solution (0.012mg/mL
Free Base, Methanol/Water [50/50])
Accurately weigh approximately 1.85 mg of 2-[(3-amino propyl)amino] ethanethiol, dihydrochloride standard into a 100-mL volumetric flask. Add 50mL of water then dilute to volume with methanol.
Shelf-Life: 24 hours at 4°C
1.3 Preparation of Amifostine (Drug Substance)
A. Assay Preparation (3mg/mL,
Methanol/Water [50/50])
Accurately weigh approximately 30.0 mg of amifostine into a 10-mL volumetric flask. Dissolve in 5 mL of water and dilute to volume with methanol.
Shelf-Life: 24 hours at 4°C
B. Related Substances (15 mg/mL, Water) Accurately weigh approximately 150.0 mg of amifostine into a 10-mL volumetric flask. Dissolve and dilute to volume with water.
Shelf-Life: 24 hours at 4°C
1.4 Preparation of Amifostine for Injection (Drug Product) (4.8mg/mL, Methanol /
Water [50/50])
Dissolve contents of one drug product vial with about 9 mL water.
Quantitatively transfer sample to 25 mL volumetric flask and dilute to volume with water. Transfer 6 mL of this solution to a 50-mL volumetric flask, add 19 mL of water and dilute to volume with methanol.
Shelf-Life: 24 hours at 4°C
2. System Suitability
Amifostine (Use Standard Solution 1.1)
% RSD of 6 Replicate Injection
of Amifostine ≤2
Tailing Factor ≤2
Theoretical Plates >1,000
2-[(3-aminopropyl)amino] ethanethiol, dichloride ("WR-1065") (Use Standard Solution 1.2)
% RSD of 6 Injections ≤4
Tailing Factor ≤2
Theoretical Plates >7,000
3. Equipment and Materials (As Stated Below or
Equivalent)
Equipment
HPLC System with UV Detector
Materials
Amifostine Standard
Concentrated Phosphoric Acid (H3PO4) : HPLC Grade
Methanol (MeOH) : HPLC Grade
Purified Water: 16 meg-ohm or greater
1-Octanesulfonic Acid, Sodium Salt (OSA) : HPLC Grade
HPLC Chromatrographic Conditions
Column Specifications:
Packing Material: TosoHaas TSK ODS-80TM,
end-capped (USP L1)
Dimensions: 4.6 × 250 mm
Particle Size: 5μm
Mobile Phase: Methanol/Aqueous Phosphoric Acid , pH3 . 0 , 3 . 5 mM OSA ( 50/ 50)
1. Dissolve 0.38g OSA in 500 mL of aqueous phosphoric acid pH 3.0
2. Dilute to 1000 mL with methanol.
3. Filter and degas the mobile phase.
Detection: 220 nm Absorbance
Flow Rate: 1.0 mL/min
Injection Volume: 10μL
Column Temperature: Ambient
Sample Temperature: 4°C
Attenuation: Adjust to produce approximately 80% full-scale amifostine peak. 4. Procedure
Inject sample and standard solutions, record retention time of the amifostine peak
(approximately 4 minutes). Retention time of the standard amifostine peak and the sample
preparation peak should agree within 10% to confirm identification of amifostine in the sample.
EXAMPLE 8: STABILITY RESULTS OF VACUUM DRIED,
CRYSTALLINE AMIFOSTINE STRESSED AT 40°C
Typical results obtained by stressing crystalline amifostine produced by the method described in Example 6 and tested as described in Example 7 is summarized in Table 4.
The above results clearly indicate the enhanced stability of the crystalline amifostine produced by
the method described in Example 6. The enhanced stability is evident from the low weight percent of thiol formation, which indicates very little
decomposition of the amifostine by hydrolysis to form 2-[(3-aminopropyl)amino] ethane thiol. Additionally, there is little loss in water content or amifostine content over time. This is in contrast to the poor stability of the vacuum dried amorphous amifostine formulation which exhibits significant decomposition within 14 days at 50°C (See Table 3 of Example 4).
EXAMPLE 9: CRYSTAL STRUCTURE OF VACUUM DRIED
AMIFOSTINE
The molecular and crystal structure of vacuum dried crystalline amifostine has been determined.
Crystal survey, unit cell determination, and data collection were performed using copper radiation at room temperature.
The structure was solved by direct methods and refined by full-matrix least-squares and difference Fourier methods. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms attached to the nitrogen and water oxygen atoms were located from difference Fourier maps and refined isotropically. The positions of the remaining hydrogen atoms were calculated assuming ideal geometries. These hydrogen atoms were not refined due to the low reflection to parameter ratio.
The compound crystallizes in the chiral space group P2,2,2,. The data presented in this example are from the enantiomeric structure with lower R values (R=0.036 and Rw=0.042). The other enantiomeric structure has an R value of 0.042 and Rw value of 0.051. A graphic depiction of the molecular and
crystal structure of vacuum dried amifostine
trihydrate is shown in Figure 13.
EXPERIMENTAL
DATA COLLECTION
A colorless flat needle-shaped crystal of
C5H21N2O6PS having approximate dimensions of 0.350 X 0.050 X 0.030 mm was mounted on a glass fiber. All measurements were made on a Rigaku AFC5R
diffractometer with graphite monochromated Cu Kα radiation and a 12KW rotating anode generator. Cell constants and an orientation matrix for data collection, obtained from a least-squares refinement using the setting angles of 20 carefully centered reflections in the range 40.45 < 2θ < 52.03°
corresponded to an orthorhombic cell with dimensions: a = 8.456 (2)Å
b = 21.553 (2)Å
c = 6.758 (2)Å
V = 1231.6 (5)Å3
For Z = 4 and F.W. = 268.26, the calculated density is 1.447 g/cm3. Based on the systematic absences of: h00: h ≠ 2n
0k0: k ≠ 2n
001: 1 ≠ 2n
and the successful solution and refinement of the structure, the space group was determined to be:
P212121 (#19)
The data were collected at a temperature of 23 ±
1°C using the ω-20 scan technique to a maximum 20 value of 120.0°. Omega scans of several intense reflections, made prior to data collection, had an average width at half-height of 0.21° with a take-off angle of 6.0°. Scans of (0.89 + 0.14 tan 0)° were made at a speed of 8.0°/min (in omega). The weak reflections (I < 15.0σ(I)) were rescanned (maximum of
4 rescans) and the counts were accumulated to assure good counting statistics. Stationary background counts were recorded on each side of the reflection. The ratio of peak counting time to background counting time was 2:1. The diameter of the incident beam collimator was 0.5 mm and the crystal to detector distance was 400.0 mm.
DATA REDUCTION
A total of 1120 reflections was collected. The intensities of three representative reflections which were measured after every 150 reflections remained constant throughout data collection indicating crystal
and electronic stability (no decay correction was applied). The linear absorption coefficient for Cu Kα is 37.1 cm-1. An empirical absorption correction, based on azimuthal scans of several reflections, was applied which resulted in transmission factors ranging from 0.89 to 1.00. The data were corrected for Lorentz and polarization effects.
EXPERIMENTAL DETAILS
A. Crystal Data
Empirical Formula C5H21N2O6PS
Formula Weight 268.26
Crystal Color, Habit colorless, flat needle
Crystal Dimensions (mm) 0.350 × 0.050 × 0.030
Crystal System orthorhombic
No. Reflections Used for Unit 20 (40.5 - 52.0°)
Cell Determination (20 range)
Omega Scan Peak Width 0.21
at Half-height
Lattice Parameters: a = 8.456 (2)Å b = 21.553 (2)Å c = 6.758 (2)Å
V = 1231.6 (5)Å3
Space Group P212121 (#19)
Z value 4
Dcalc 1.447 g/cm3
F000 576
μ(CuKα) 37.10 cm-1
B. Intensity Measurements
Diffractometer Rigaku AFC5R
Radiation CuKα (λ = 1.54178 Å)
Temperature 23°C
Attenuators Zr (foil L factors: 3.8,
13.4, 47.8)
Take-off Angle 6.0°
Detector Aperture 6.0 mm horizontal
6.0 mm vertical
Crystal to Detector 40 cm
Distance
Scan Type ω-2θ
Scan Rate 8.0°/min (in omega)
(4 rescans)
Scan Width (0.89 + 0.14 tanθ)° 2θmax 120.0°
No. of Reflection Total: 1120
Measured
Corrections Lorentz-polarization
Absorption
(trans. factors:
0.89 - 1.00) C. Structure Solution and Refinement
Structure Solution Direct methods
Refinement Full-matrix
least-squares
Function Minimized Σ w (╎Fo╎ - ╎Fc╎)2 Least-squares Weights 4Fo2/σ2 (Fo2)
p-factor 0. 03
Anomalous Dispersion All non-hydrogen atoms
No. Observations 856
(I>3.00σ(I))
No. Variables 180
Reflection/Parameter 4.76
Ratio
Residuals: R; Rw 0.036; 0.042
Goodness of Fit 1.37
Indicator
Max Shift/Error in 0.00
Final Cycle
Maximum Peak in Final 0.30 e-/Å3
Diff. Map
Maximum Peak in Final -0.22 e-/Å3
Diff. Map
Positional parameters and B (eq) for C(5)H(21)N(2)0(6)P(1)S(1)
atom x y z B(eq) S(1) 0.5773(2) 0.67451(7) 0.3809(3) 3.13(6) P(1) 0.5106(2) 0.59073(6) 0.2413(2) 2.14(5) O(1) 0.3359(4) 0.5965(2) 0.1901(6) 2.8(2)
O(2) 0.5390(5) 0.5383(2) 0.3868(7) 3.1(2) O(3) 0.6192(4) 0.5882(2) 0.0644(6) 3.2(2) O(4) 0.8435(6) 0.6830(3) 0.970(1) 4.7(3) O(5) 1.1634(7) 0.7064(3) 0.097(1) 4.5(3) O(6) 1.2270(6) 0.5451(2) 0.8548(8) 4.0(2) N(1) -0.1325(6) 0.4983(2) 0.2650(9) 2.4(2) N(2) 0.2036(6) 0.6289(2) 0.5503(9) 2.6(2) C(1) -0.0319(7) 0.554(3) 0.2978(9) 2.8(3) C(2) -0.0611(7) 0.5820(3) 0.5004(9) 2.9(3) C(3) 0.0296(7) 0.6415(3) 0.537(1) 2.9(3) C(4) 0.2965(7) 0.6853(3) 0.604(1) 3.0(3) C(5) 0.4721(7) 0.6719(3) 0.615(1) 3.4(3) H(1) 0.796(8) 0.716(3) 0.94(1) 4(1) H(2) 0.77(1) 0.650(4) 1.00(1) 10(2) H(3) 1.08(1) 0.699(4) 0.04(1) 6(2) H(4) 1.215(9) 0.675(3) 0.11(1) 5(2)
Positional parameters and B (eq) for C(5)H(21)N(2)O(6)P(1)S(1)
atom x y z B(eq)
H(5) 1.147(8) 0.521(3) 0.87(1) 4(1)
H(6) 1.27(1) 0.559(4) 0.98(2) 10(2)
H(7) -0.24(1) 0.513(3) 0.28(1) 4(1)
H(8) -0.110(8) 0.484(3) 0.14(1) 4(1)
H(9) -0.104(8) 0.466(3) 0.34(1) 4(1)
H(10) 0.227(9) 0.594(4) 0.65(1) 7(2)
H(11) 0.234(7) 0.617(2) 0.443(9) 2(1) H(12) -0.0561 0.5845 0.1998 3.4
H(13) 0.0763 0.5429 0.2873 3.4
H(14) -0.1709 0.5905 0.5130 3.4
H(15) -0.0306 0.5524 0.5974 3.4
H(16) 0.0103 0.6696 0.4318 3.5 H(17) -0.0052 0.6594 0.6582 3.5
H(18) 0.2787 0.7165 0.5077 3.6
H(19) 0.2617 0.6998 0.7299 3.6
H(20) 0.5188 0.7016 0.7010 4.1
H(22) 0.4852 0.6315 0.6694 4.1
It should be apparent to one of ordinary skill that other embodiments not specifically disclosed nonetheless fall within the scope and spirit of the present invention. Hence, the descriptions herein should not be taken as limiting the invention in any way, except as stated in the following claims.
Claims (12)
1. A process for the preparation of a
crystalline amifostine composition comprising the steps of:
(a) preparing a formulation comprising
amifostine, ethanol and water in which the relative amounts of amifostine, ethanol and water are such that a particulate-free solution is obtained at temperatures ranging from about room temperature to about 10°C, but which provides a crystalline precipitate of amifostine upon cooling below 0°C;
(b) cooling said formulation to a temperature below 0°C for a period of time sufficient to effect the
precipitation of the crystalline amifostine; and
(c) vacuum drying the resulting mixture to leave a solid crystalline amifostine preparation having enhanced stability.
2. The process of claim 1 which further comprises introducing a sterile inert gas over said preparation after completion of the vacuum drying of step (c).
3. The process of claim 2 in which said inert gas is selected from the group consisting of argon, nitrogen and helium.
4. The process of claim 1 in which the
temperature of step (b) is about a eutectic point of said formulation.
5. The process of claim 4 which further
comprises, after step (b), raising the temperature of the resulting mixture to an annealing temperature that lies about 1 to about 20°C above said eutectic
temperature, followed by cooling the temperature of said mixture from said annealing temperature back to said eutectic temperature or below prior to performing step (c).
6. The process of claim 4 in which said
eutectic temperature falls in the range of about 0°C to about -80 °C.
7. The process of claim 5 in which said
annealing temperature falls in the range of about -30°C to about 10°C and said eutectic temperature falls in the range of about 0°C to about -80°C.
8. The process of claim 1 in which said
formulation comprises about 50 to about 400 mg
amifostine per ml of formulation, about 1-35% (v/v) ethanol, and about 65-99% (v/v) water.
9. The process of claim 1 in which said
formulation comprises about 125 to about 250 mg amifostine per ml of formulation, about 5-20% (v/v) ethanol, and about 80-95% (v/v) water.
10. The process of claim 1 in which said
formulation comprises about 100 mg amifostine per ml of formulation, about 10% (v/v) ethanol, and about 90% (v/v) water.
11. The process of claim 1 in which said
temperature of step (b) falls in the range of about -5°C to about -40°C. 12. The process of claim 1 in which said
temperature of step (b) is about -20°C.
13. The process of claim 1, 4 or 5 which further comprises a sterilization step.
14. The process of claim 13 in which said sterilization step comprises sterile filtering said formulation of step (a) prior to cooling. 15. The process of claim 1, 4, 5 or 14 in which said crystalline amifostine is a hydrate of
amifostine.
16. The process of claim 1, 4, 5 or 14 in which said crystalline amifostine is an amifostine
trihydrate.
17. The process of claim 1, 4, 5 or 14 in which said crystalline amifostine contains from about 1 mole to about 3 moles of water of crystallization.
18. The process of claim 1, 4, 5 or 14 in which said formulation further comprises a pharmaceutically acceptable excipient.
19. The process of claim 18 in which said excipient is selected from the group consisting of sodium chloride, glycine, dextrose, sucrose and mannitol.
20. The process of claim 18 in which said excipient is mannitol.
21. A process for the preparation of a
crystalline amifostine composition comprising the steps of:
(a) preparing a formulation comprising
about 50 to about 300 mg amifostine per ml of said formulation, about 3 to about 30% (v/v) ethanol, about 70-97%
(v/v) water, and, optionally, about 5 to about 300 mg of a pharmaceutically acceptable excipient per ml of said formulation such that a particulate- free solution is obtained at
temperatures ranging from about room temperature to about 10°C but which provides a crystalline precipitate of amifostine upon cooling below 0°C;
(b) cooling said formulation to a temperature falling in the range of about -5°C to about -40°C for a period of time sufficient to effect the precipitation of the crystalline amifostine; and
(c) vacuum drying the resulting mixture to leave a solid crystalline amifostine preparation having enhanced stability.
22. The process of claim 1, 4, 5 or 21 in which the step(s) taken after step (a) and before step (c) are carried out over a period of about 0.5 to about 72 hours.
23. The process of claim 1, 4, 5 or 21 in which the step(s) taken after step (a) and before step (c) are carried out over a period of about 2 to about 24 hours.
24. The process of claim 1, 4, 5 or 21 in which step (c) is carried out over a period of about 1 to about 72 hours.
25. The process of claim 1, 4, 5 or 21 in which step (c) is carried out over a period of about 10 to about 20 hours.
26. The process of claim 1, 4, 5 or 21 in which step (c) is carried out at a vacuum of about 10 to about 1000 mTorr.
27. The process of claim 1, 4, 5 or 21 in which step (c) is carried out at a vacuum of about 150 mTorr. 28. A crystalline amifostine composition having enhanced stability prepared according to the process of claim 1, 4, 5, 13, 18 or 21.
29. A method of treating a subject in need of radio- or chemoprotection comprising administering to said subject an effective amount of a crystalline amifostine composition of claim 28 which has been reconstituted with a pharmaceutically acceptable vehicle.
30. The method of claim 29 in which said reconstituted pharmaceutical composition is
administered parenterally.
31. The method of claim 29 in which said
reconstituted pharmaceutical composition is
administered intravenously, intramuscularly,
subcutaneously, intracavetarily, or intrathecally.
32. A sterile composition having an enhanced stability comprising vacuum dried crystalline
amifostine which can be reconstituted with a
pharmaceutically acceptable vehicle into an injectable particulate-free drug product.
33. The sterile composition of claim 32 which further comprises a pharmaceutical excipient. 34. The sterile composition of claim 33 in which said excipient is selected from the group consisting of sodium chloride, glycine, dextrose, sucrose and mannitol. 35. The sterile composition of claim 32 in which said vehicle is Water for Injection, USP, or normal saline.
36. The sterile composition of claim 32 in which said crystalline amifostine is a hydrate of
amifostine.
37. The sterile composition of claim 32 in which said crystalline amifostine is an amifostine
trihydrate.
38. The sterile composition of claim 32 in which said crystalline amifostine contains from about 1 mole to about 3 moles of water of crystallization.
39. A sterile single dose formulation of vacuum dried crystalline amifostine having enhanced stability comprising about 10 to about 10,000 mg vacuum dried crystalline amifostine and, optionally, about 10 to about 10,000 mg of a pharmaceutically acceptable excipient, which formulation can be reconstituted with a pharmaceutically acceptable vehicle into an
injectable particulate-free drug product. 40. The sterile single dose formulation of claim 39 comprising about 100-1000 mg vacuum dried
crystalline amifostine and about 100-1000 mg mannitol.
41. The sterile single dose formulation of claim 39 comprising about 500 mg vacuum dried crystalline amifostine and about 500 mg mannitol.
42. A method of treating a subject in need of radio- or chemoprotection comprising administering to said subject an effective amount of a reconstituted sterile composition of claim 32 or 33.
43. A method of treating a subject in need of radio- or chemoprotection comprising administering to said subject an effective amount of a reconstituted single dose formulation of claim 39 or 40.
44. A vacuum dried amifostine having enhanced stability.
45. The vacuum dried amifostine of claim 44 wherein the amifostine is a trihydrate.
46. The vacuum dried amifostine of claim 44 wherein the amifostine is crystalline.
47. The vacuum dried amifostine of claim 46 wherein the amifostine is a trihydrate.
48. Crystalline amifostine trihydrate having substantially the crystal structure described in
Example 9.
49. A process for the preparation of a
crystalline amifostine composition comprising the steps of:
(a) preparing a formulation comprising
about 100 mg amifostine per mL of said formulation, about 100 mg of a
pharmaceutically acceptable excipient per mL of said formulation, and about
12.5% (v/v) ethanol in water solution such that a particulate free solution is obtained at about room temperature;
(b) cooling said formulation from room
temperature to about -35°C in about 160 minutes;
(c) maintaining said formulation at about -35 °C for about 240 minutes to form seeds of crystalline amifostine;
(d) warming said formulation to about 0°C in about 25 minutes;
(e) maintaining said formulation at about 0°C for about 600 minutes to anneal the seeds and precipitate crystalline amifostine;
(f) cooling said formulation from about 0°C to about -15°C in about 15 minutes;
(g) cooling said formulation from about -15°C to about -35°C in about 120 minutes; (h) maintaining said formulation at about
-35°C for about 180 minutes;
(i) evacuating the air around said
formulation to a pressure less than about 150 microns;
(j) warming said formulation from about
-35°C to about -20°C over about 54 hours;
(k) maintaining said formulation at about -20°C for about 12 to about 24
additional hours to leave a crystalline amifostine composition having enhanced stability.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US099298 | 1979-12-03 | ||
US92292992A | 1992-07-31 | 1992-07-31 | |
US922929 | 1992-07-31 | ||
US08/099,298 US5424471A (en) | 1992-07-31 | 1993-07-29 | Crystalline amifostine compositions and methods of the preparation and use of same |
PCT/US1993/007222 WO1994003179A1 (en) | 1992-07-31 | 1993-07-30 | Crystalline amifostine compositions and methods for the preparation and use of same |
Publications (2)
Publication Number | Publication Date |
---|---|
AU4796693A true AU4796693A (en) | 1994-03-03 |
AU681858B2 AU681858B2 (en) | 1997-09-11 |
Family
ID=26795942
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU47966/93A Expired AU681858B2 (en) | 1992-07-31 | 1993-07-30 | Crystalline amifostine compositions and methods for the preparation and use of same |
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US (1) | US5591731A (en) |
EP (1) | EP0655917B1 (en) |
JP (1) | JP3503943B2 (en) |
CN (2) | CN1070370C (en) |
AT (1) | ATE261729T1 (en) |
AU (1) | AU681858B2 (en) |
CA (1) | CA2120133C (en) |
CZ (1) | CZ284417B6 (en) |
DE (1) | DE69333453T2 (en) |
DK (1) | DK0655917T3 (en) |
ES (1) | ES2215992T3 (en) |
HK (1) | HK1010692A1 (en) |
HU (1) | HU227122B1 (en) |
IL (1) | IL106540A (en) |
IS (1) | IS1843B (en) |
MX (1) | MX9304627A (en) |
NO (2) | NO309636B1 (en) |
NZ (1) | NZ255182A (en) |
PL (1) | PL178463B1 (en) |
PT (1) | PT655917E (en) |
RU (1) | RU2125880C1 (en) |
SG (1) | SG47101A1 (en) |
SK (1) | SK283318B6 (en) |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6573253B2 (en) | 1997-02-12 | 2003-06-03 | Medimmune Oncology Inc. | Methods for the administration of amifostine and related compounds |
US6051563A (en) | 1997-02-12 | 2000-04-18 | U.S. Bioscience, Inc. | Methods for the administration of amifostine and related compounds |
US5994409A (en) * | 1997-12-09 | 1999-11-30 | U.S. Bioscience, Inc. | Methods for treatment of neuro--and nephro--disorders and therapeutic toxicities using aminothiol compounds |
US6239119B1 (en) | 1998-04-27 | 2001-05-29 | Medimmune Oncology, Inc. | Topical administration of amifostine and related compounds |
US6017922A (en) | 1998-05-18 | 2000-01-25 | U.S. Bioscience, Inc. | Thermally stable trimetrexates and processes for producing the same |
US6384259B1 (en) * | 1998-11-16 | 2002-05-07 | Medimmune Oncology, Inc. | Stable amorphous amifostine compositions and dosage form |
US6407278B2 (en) | 1998-11-16 | 2002-06-18 | Medimmune Oncology, Inc. | Stable amorphous amifostine compositions and methods for the preparation and use of the same |
DE10043170C2 (en) * | 2000-09-01 | 2002-10-24 | Klinge Co Chem Pharm Fab | Amifostine monohydrate and process for its preparation |
CN1148192C (en) * | 2000-10-19 | 2004-05-05 | 南京振中生物工程有限公司 | Cell-protecting amifostine and its preparing process |
US7053072B2 (en) | 2001-05-11 | 2006-05-30 | Medimmune Oncology, Inc. | Methods for the administration of amifostine and related compounds |
AU2003217676B2 (en) | 2002-02-22 | 2009-06-11 | Takeda Pharmaceutical Company Limited | Active agent delivery systems and methods for protecting and administering active agents |
US7629333B2 (en) * | 2002-03-29 | 2009-12-08 | Medimmune, Llc | Stable amorphous amifostine compositions and methods for the preparation and use of same |
CN1305478C (en) * | 2004-05-12 | 2007-03-21 | 天津市资福医药科技开发有限公司 | Freeze drying preparation of amifostine, and preparation method |
PL2987796T3 (en) | 2005-02-16 | 2018-12-31 | Anacor Pharmaceuticals, Inc. | Halogen-substituted boronophthalides for the treatment of infections |
WO2007047315A1 (en) * | 2005-10-20 | 2007-04-26 | Albemarle Corporation | Amifostine dihydrate crystalline composition |
US8158152B2 (en) * | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
WO2007078340A2 (en) | 2005-12-30 | 2007-07-12 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
MX360301B (en) | 2006-02-16 | 2018-10-29 | Anacor Pharmaceuticals Inc | Boron-containing small molecules as anti-inflammatory agents. |
US9585849B2 (en) | 2006-04-17 | 2017-03-07 | The Burlington Hc Research Group, Inc. | Broad spectrum antiviral and methods of use |
EP2010166B1 (en) * | 2006-04-17 | 2013-11-06 | The Government of the United States of America as represented by the Secretary of the Department of Health and Human Services | Organic disulfide antiretroviral agents |
WO2008060441A2 (en) * | 2006-11-09 | 2008-05-22 | Scidose Llc | Stable amifostine liquid concentrate |
MX2010009765A (en) | 2008-03-06 | 2013-07-12 | Anacor Pharmaceuticals Inc | Boron-containing small molecules as anti-inflammatory agents. |
EP2285384A4 (en) * | 2008-05-12 | 2012-04-25 | Anacor Pharmaceuticals Inc | Boron-containing small molecules |
CN101412732B (en) * | 2008-09-02 | 2011-09-07 | 大连美罗药业股份有限公司 | Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof |
CN101347412B (en) * | 2008-09-02 | 2011-07-27 | 大连美罗药业股份有限公司 | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same |
WO2010027975A1 (en) * | 2008-09-04 | 2010-03-11 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
US8461336B2 (en) | 2008-09-04 | 2013-06-11 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
WO2010045503A1 (en) * | 2008-10-15 | 2010-04-22 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as anti-protozoal agents |
MX2011006334A (en) * | 2008-12-17 | 2011-09-22 | Anacor Pharmaceuticals Inc | Polymorphs of (s)-3-aminomethyl-7-(3-hydroxy-propoxy)-3h-benzo[c] [1,2] oxaborol-1-ol. |
MX2012001156A (en) * | 2009-07-28 | 2012-05-08 | Anacor Pharmaceuticals Inc | Trisubstituted boron-containing molecules. |
US9440994B2 (en) * | 2009-08-14 | 2016-09-13 | Anacor Pharmaceuticals, Inc. | Boron containing small molecules as antiprotozoal agents |
US20110207701A1 (en) * | 2009-08-19 | 2011-08-25 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as antiprotozoal agents |
WO2011037731A1 (en) * | 2009-09-25 | 2011-03-31 | Anacor Pharmaceuticals, Inc. | Boron containing small molecules |
WO2011049971A1 (en) | 2009-10-20 | 2011-04-28 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as antiprotozoal agents |
US8461134B2 (en) * | 2009-11-11 | 2013-06-11 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
RS56634B1 (en) * | 2009-11-20 | 2018-03-30 | Tonix Pharma Holdings Ltd | Methods and compositions for treating symptoms associated with post-traumatic stress disorder using cyclobenzaprine |
US8716478B2 (en) | 2010-01-27 | 2014-05-06 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules |
WO2011116348A1 (en) | 2010-03-19 | 2011-09-22 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as anti-protozoal agent |
US20110319389A1 (en) | 2010-06-24 | 2011-12-29 | Tonix Pharmaceuticals, Inc. | Methods and compositions for treating fatigue associated with disordered sleep using very low dose cyclobenzaprine |
EA028743B1 (en) | 2010-09-07 | 2017-12-29 | Анакор Фармасьютикалс, Инк. | Benzoxaborole derivatives as antibacterial agents |
US11998516B2 (en) | 2011-03-07 | 2024-06-04 | Tonix Pharma Holdings Limited | Methods and compositions for treating depression using cyclobenzaprine |
TWI432204B (en) * | 2011-06-03 | 2014-04-01 | Taiwan Hopax Chems Mfg Co Ltd | Pharmaceutical compositions against free radicals |
CN102286020A (en) * | 2011-07-11 | 2011-12-21 | 大连美罗大药厂 | Method for preparing 3-aminopropyl amine ethyl thiophosphoric acid monohydrate |
FI3650081T3 (en) | 2013-03-15 | 2024-05-16 | Tonix Pharma Holdings Ltd | Eutectic formulations of cyclobenzaprine hydrochloride and mannitol |
EP3011339A4 (en) * | 2013-06-18 | 2017-01-25 | Aminomedix Inc. | Compositions and methods for the preparation of kidney protective agents comprising amifostine and amino acids |
BR112017005231A2 (en) | 2014-09-18 | 2018-03-13 | Tonix Pharma Holdings Ltd | eutectic formulations of cyclobenzaprine hydrochloride |
EP3200805A4 (en) * | 2014-10-02 | 2018-07-11 | Cytosorbents Corporation | Use of gastrointestinally administered porous enteron sorbent polymers to prevent or treat radiation induced mucositis, esophagitis, enteritis, colitis, and gastrointestinal acute radiation syndrome |
US11447506B2 (en) | 2016-05-09 | 2022-09-20 | Anacor Pharmaceuticals, Inc. | Crystal forms of crisaborole in free form and preparation method and use thereof |
SG11202004799TA (en) | 2017-12-11 | 2020-06-29 | Tonix Pharma Holdings Ltd | Cyclobenzaprine treatment for agitation, psychosis and cognitive decline in dementia and neurodegenerative conditions |
CN110735176B (en) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | Method for preparing coordination compound monocrystal or amorphous substance |
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CN110735177B (en) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | Method for preparing monocrystal or amorphous substance by utilizing solution freezing |
CN110607551B (en) * | 2018-10-30 | 2024-02-20 | 中国科学院化学研究所 | Method for preparing food additive monocrystal or amorphous substance |
CN110606868A (en) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | Method for preparing polypeptide or protein single crystal or amorphous substance |
WO2020088479A1 (en) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | Method for using aqueous solution to prepare single crystal or amorphous substance |
CN110616463B (en) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | Method for preparing organic semiconductor molecule monocrystal or amorphous substance |
EP3824880A1 (en) * | 2019-11-25 | 2021-05-26 | Clevexel Pharma | Freeze-dried powder containing 2-[(3-aminopropyl)amino]ethanethiol and its use for preparing a thermogel |
KR20240041506A (en) * | 2022-09-23 | 2024-04-01 | 주식회사 경보제약 | Stable monohydrate form of avibactam sodium and manufacturaing method thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3892824A (en) * | 1968-12-16 | 1975-07-01 | Southern Res Inst | S-{107 -({107 -aminoalkylamino)alkyl dihydrogen phosphorothioates |
JPS6041676B2 (en) * | 1977-09-21 | 1985-09-18 | 山之内製薬株式会社 | New method for producing S-2-(3-aminopropylamino)ethyldihydrodiene phosphorothioate monohydrate crystals |
US4424216A (en) * | 1979-07-31 | 1984-01-03 | The Rockefeller University | Method for the reduction of mucin viscosity |
AU4674385A (en) * | 1984-08-08 | 1986-03-07 | Survival Technology Inc. | Absorption enhancing agents |
WO1990014007A1 (en) * | 1989-05-24 | 1990-11-29 | U.S. Bioscience | Method for protection from azt side effects and toxicity |
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- 1993-06-30 SG SG1996007320A patent/SG47101A1/en unknown
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